3-Substituted 2,4,6-trihalogenated benzamides as sweetening agents

ABSTRACT

The 3-substituted 2,4,6-trihalogenated benzamides having the formula I ##STR1## wherein Hal is chlorine, bromine, or iodine and 
     Z is a carboxyl group or the group ##STR2## wherein P is 1 and L is 0 or 1, with the proviso that L is 0 when K is 0; K is 0, 2, 3, or 4; 
     M is 0, 1, 2 or 3; 
     N is 0 or 1; 
     X is a hydrogen atom; 
     Y is a hydrogen atom or a lower alkyl group of 1-4 carbon atoms, or when either M or N is other than 0, a hydroxy group, a C 1-6  alkoxy group or a C 1-4  acyloxy group, or when N is 1 and M is other than 0, X and Y together represent an additional carbon-carbon bond; 
     or P and L are each 0; p1 K is 0, 2, 3 or 4; 
     M is 0, 1, 2 or 3; 
     N is 0 or 1; 
     X is a hydrogen atom; 
     Y is a hydrogen atom, a lower alkyl group of 1-4 carbon atoms, a hydroxy group, a C 1-6  alkoxy group, a C 1-4  acyloxy group or, when N is 1, X and Y together represent an additional carbon-carbon bond; 
     and salts thereof with inorganic bases, exhibit an extraordinarily high sweetening power and are excellent substitutes for natural sweetening agents.

BACKGROUND OF THE INVENTION

This invention relates to 3-substituted 2,4,6-trihalogenated benzamidesand their use as sweetening agents.

The so-called synthetically produced "sweeteners" with a far highersweetening effect than cane sugar (sucrose) have been known for a longtime. The most well-known representatives of this class of substancesare saccharin, Dulcin, and sodium cyclamate, as well as "Aspartame" and2-amino-4-nitro-1-phenyl-n-propyl ether ("Ultrasuss", P 4000).

Synthetic sweeteners should exhibit, besides a high degree of sweetening(low-load compound), no side effects and a very high compatibility.Furthermore, they must be able to withstand without changes the thermalstresses during the cooking or baking process. A lack of heat stability,for example, limits the range of applications of "Aspartame" to a greatextent; and the objections from a health viewpoint existing againstDulcin resulted in prohibition of the use of Dulcin, for example, in theFederal Republic of Germany and in the United States of America.

Compounds of formula I wherein

Hal is iodine and Z is the group ##STR3## wherein P is 1 and K, L, M are0; N is 0;

Y is --CH₃, --C₂ H₅, --C₄ H₉, --Phenyl;

or N is 1 or 2;

X and Y are a hydrogen atom

and salts thereof with bases are disclosed in the DAS 1 568 959. Theyare disclosed to be suitable for use as opacifiers in cholecystographyand as choleretics.

The need is great for artificial sweeteners having a stronger degree ofsweetening and a further improved general compatibility, both formedical reasons (diabetics) and for dietetic reasons (reduction ofcalories).

SUMMARY OF THE INVENTION

The present invention relates to 3-substituted 2,4,6-trihalogenatedbenzamides, having the formula I ##STR4## wherein (A) Hal is a chlorineor bromine atom; and

Z is a carboxyl group, or represents the group ##STR5## wherein P and Lare each independently 0 or 1, with the proviso that L is 0 when eitherP or K is 0;

K is 0, 2, 3 or 4;

M is 0, 1, 2 or 3;

N is 0 or 1;

X is a hydrogen atom;

Y is a hydrogen atom or a lower alkyl group of 1-4 carbon atoms or, wheneither M or N is other than 0, an optionally etherified or esterifiedhydroxy group, or when N is 1 and M is other than 0, X and Y togetherform an additional carbon-carbon bond;

or wherein

(B) Hal is an iodine atom; and

Z is a carboxyl group, or represents the group ##STR6## wherein (1) Pand L are each 0; K is 0, 2, 3 or 4;

M is 0, 1, 2 or 3;

N is 0 or 1;

X is a hydrogen atom;

Y is a hydrogen atom, a lower alkyl group of 1-4 carbon atoms, or anoptionally etherified or esterified hydroxy group, or when N is 1 and Mis other than 0, X and Y together form an additional carbon-carbon bond;

or (2) P and L are each 1;

K is 2, 3 or 4;

M is 0, 1, 2 or 3;

N is 0 or 1;

X is a hydrogen atom; and

Y is a hydrogen atom or a lower alkyl group of 1-4 carbon atoms;

or (3) P is 1;

L is 0;

K, M and N are each 0; and

Y is a hydrogen atom;

or (4) P is 1;

L is 0;

K is 0;

M is 1 or 2;

N is 0; and

Y is a lower alkyl residue of 1-4 carbon atoms;

or (5) P is 1;

L is 0;

K is 2, 3, or 4;

M is 0, 1, 2 or 3;

N is 1;

X is a hydrogen atom; and

Y is a hydrogen atom or a lower alkyl residue of 1-4 carbon atoms;

and salts thereof with inorganic bases.

In addition, the present invention relates to sweeteners comprising acompound having the formula I ##STR7## wherein Hal is chlorine, bromine,or iodine and

Z is a carboxyl group or the group ##STR8## wherein P is 1 and L is 0 or1 with the proviso that L is 0 when K is 0;

K is 0, 2, 3 or 4;

M is 0, 1, 2 or 3;

N is 0 or 1;

X is a hydrogen atom;

Y is a hydrogen atom or a lower alkyl group of 1-4 carbon atoms, or wheneither M or N is other than 0, a hydroxy group, a C₁₋₆ alkoxy group or aC₁₋₄ acyloxy group; or, when N is 1 and M is other than 0, X and Ytogether represent an an additional carbon-carbon bond;

or P and L are 0

K is 0, 2, 3 or 4;

M is 0, 1, 2 or 3;

N is 0 or 1;

X is a hydrogen atom,

Y is a hydrogen atom, a lower alkyl group of 1-4 carbon atoms, a hydroxygroup, a C₁₋₆ alkoxy group, a C₁₋₄ acyloxy group or, when N is 1, X andY together represent an additional carbon-carbon bond;

and salts thereof with inorganic bases, in combination with a non-toxicvehicle.

In a method of use aspect, the present invention relates to the use ofthe foregoing compounds in place of known sweetening agents wheneversuch agents are used to impart a sweet taste to a composition, formedical or dietetic purposes or simply for flavoring food, drink orother composition to be ingested by mouth.

DETAILED DISCUSSION

In the compounds of formula I, suitable lower alkyl groups Y are alkylresidues of 1-4 carbon atoms, the methyl and ethyl residues beingpreferred. When Y is an optionally etherified hydroxy group, it isetherified with an alkyl residue of 1-6 carbon atoms, the methyl, ethyl,and n-pentyl residues being preferred.

When Y is an esterified hydroxy group, it is esterified with a C₁₋₄lower carboxylic acid of 1-3 carbon atoms in the alkyl moiety, aceticacid and propionic acid being preferred.

When Z is --COOH or the group ##STR9## the following residues arepreferred: --CH₂ --COOH, --(CH₂)₂ --COOH, ##STR10## --O--CH₂ CH₂--O--CH₂ --COOH, --O--(CH₂)₃ --COOH --O--(CH₂)₂ --O--CH₂ --CH═CH--COOH.

The compounds of formula I, including the novel compounds of formulaeI(A) and I(B) are thermally stable, crystalline compounds and exhibit,as the acid and also in the form of their neutral salts with inorganicbases, an extraordinarily strong sweetening power. They possess theproperties required of artificial sweeteners to a surprisingly highdegree; for example, the sodium salt of3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid (A) exhibits6000-7000 times the sweetening power of sucrose (cane sugar) and in thisrespect also surpasses sodium saccharin and sodium cyclamate, as borneout by the following tests.

Determination of the Sweetening Power

(a) For determining the sweetening power, an aqueous 5% (g/v) (% g/v isthe number of grams of agent in 100 ml of solution) sucrose solution wascompared with aqueous solutions of the sodium salt of3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid (A) as well as sodiumsaccharin and sodium cyclamate in up to eight concentration stages withthe use of taste tests. The 0.05% solutions (concentration stage 1),from which all further solutions were prepared by dilution with water(1+1), had a pH of 5-7.

The following concentrations correspond to the 8 concentration stagestested:

    ______________________________________                                                                 Concentration                                                                 Ratio with                                                                    Respect to 5%                                        Concentration                                                                              Concentration                                                                             Sucrose                                              Stage No.    (mg/100 ml) Solution                                             ______________________________________                                        1            50.0        1/100                                                2            25.0        1/200                                                3            12.5        1/400                                                4            6.25        1/800                                                5            3.125        1/1600                                              6            1.563        1/3200                                              7            0.781        1/6400                                              8            0.391        1/12800                                             ______________________________________                                    

                                      TABLE 1                                     __________________________________________________________________________    General Taste Evaluation and Degree of Sweetening of the Sodium Salt of       3-(3-Carbamoyl-2,4,6-                                                         tribromophenyl)propionic Acid (A) as Compared with Sucrose, Sodium            Saccharin, and Sodium Cyclamate                                               General Taste Evaluation* in Concentration Stages 1-8                         Compound                                                                            1    2   3    4    5   6   7   8    Degree of Sweetening*               __________________________________________________________________________    Sucrose                                                                             --   --  --   --   --  --  --  --    1                                  Sodium                                                                              Sweet                                                                              Sweet                                                                             Slightly                                                                           Very --  --  --  --   400                                 Saccharin      Sweet                                                                              Slightly                                                                      Sweet                                                     Cyclamate                                                                           Very NT  NT   NT   --  --  --  --   <100**                                    Slightly                                                                      Sweet                                                                   A     Very,                                                                              Very                                                                              Very Very Very                                                                              Sweet                                                                             Sweet                                                                             Slightly                                                                           6000-7000                                 Very Sweet                                                                             Sweet                                                                              Sweet                                                                              Sweet       Sweet                                          Sweet                                                                   __________________________________________________________________________     *Average results of 3 taste tests; NT = no taste.                             **As per literature: 30-70                                               

The taste tests were conducted by three healthy volunteers; thesolutions were coded by letter-number combinations and randomized sothat the tester could not know which compound he or she tasted. Also thereference solution (5% sucrose) remained part of the randomizing planinitially, for the purpose of general taste characteristics of thecompounds. The estimation of the degree of sweetening then took place ina second test series wherein the coding of the reference solution wasrevealed.

The general taste evaluation of the tested compounds and the degree ofsweetening are indicated in Table 1. Since the degrees of sweetening ofsodium saccharin (400) and of sodium cyclamate (70) known from theliterature (see "Hager's Manual of Practical Pharmacology", 4th Ed., VIIB (1977), Springer Publishers, page 426) were also determined withcertainty by all three testers in a blind taste test, these results canbe considered a basis for the reliability of the test results of thetest compound.

(b) Another sensory test series confirmed the extraordinarily highsweetening power of the compounds of Formula I as compared with priorart compounds. In this testing series, the identification thresholdvalues (c_(ts)) of compounds of this invention according to formula I,viz.,

    3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid         (A)

    3-(3-carbamoyl-2,4,6-triiodophenyl)propionic acid          (E)

    3-carbamoyl-2,4,6-triiodophenoxyacetic acid                (F)

    3-(3-carbamoyl-2,4,6-trichlorophenyl)propionic acid        (G)

and of compounds of the prior art, viz., sodium saccharin, cyclamate,Dulcin, and Aspartame, were determined and compared with the value forsucrose as the natural sweetening agent.

These sensory investigations were conducted by 5 persons; all sampleswere encoded by a person not participating in the test. The compoundswere dissolved in tap water; if necessary, the pH value was set at 6-7with NaOH. Consecutive samples of 1 ml were consumed.

The approximate concentration values determined in a preliminary testwere inserted, in the main experiment, in the middle of a dilutionseries. All solutions of a compound were encoded with two water samples(triangle test). The testers must indicate which of the three samples ofdecreasing concentration are considered to be sweet. The identificationthreshold value is set forth to be the lowest concentration range(c_(ts)) at which the testers still render a correct judgment.

The identification threshold values c_(ts) (μmol/l) for the compounds A,E, F, and G of this invention, as well as for sodium saccharin,cyclamate, Dulcin, Aspartame, and sucrose (cane sugar) as the comparisoncompounds, are compiled in Table 2. If the quotient is formed from thec_(ts) values of the respective compound and the c_(ts) value forsucrose: ##EQU1## then a value f is obtained, indicating how much higherthe sweetening power of the tested compound is compared with sucrose.These f_(suc) values are also compiled in Table 2.

                  TABLE 2                                                         ______________________________________                                        Identification Threshold Values (c.sub.ts) of Several Sweeteners              Compound   MW        (μmol/l)                                                                              f.sub.suc, mol (c.sub.ts)                     ______________________________________                                        G          296.54    2.5-4.0    3385                                          A          451.89    0.6-1.4    11000                                         E          570.88    1.0-2.0    7333                                          F          584.92    15-25      550                                           Sodium Saccharin                                                                         183.19    15-30      489                                           Cyclamate  201.22    1000-3000  5.5                                           Dulcin     180.2     15-30      489                                           Aspartame  294.3     20-60      275                                           Sucrose    342.3     10000-12000                                                                              1                                             ______________________________________                                    

It can be seen from Table 2 that the compounds A, E, F, and G of thisinvention possess a greater sweetening power (f≧550) than sodiumsaccharin (f=489), the strongest artificial sweetener known heretofore.

The compounds of formula I according to this invention moreover exhibitan excellent general compatibility. As can be seen from Table 3, withintraperitoneal injection in mice, the sodium salt of3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid (A) showsapproximately the same good compatibility as sodium saccharin.

                  TABLE 3                                                         ______________________________________                                                               Finding                                                                       (Number of Dead                                        Test         Dose      Animals/Number of                                      Compound     (g/kg BW) Animals Utilized)                                      ______________________________________                                        A            3.0       2/10                                                                6.0       6/10                                                                9.0       10/10                                                  Sodium       3.0       0/10                                                   Saccharin    6.0       5/10                                                                10.0      9/10                                                   ______________________________________                                    

According to these results, the LD₅₀ after a one-time intraperitonealadministration of sodium saccharin and of compound A is approximately at6.0 g/kg body weight. The LD₅₀ found for sodium saccharin agrees withthe LD₅₀ after i.p. administration to mice reported previously byTaylor, et al., in "Toxicological Studies with Sodium Cyclamate andSaccharin" Fd. Cosmet. Toxicol., 6, 313-327 (1968). Insofar as itspractical utilization as a substitute compound for sodium saccharin,this good compatibility of compound A, which here can be estimated onlyroughly, must be considered to be very advantageous since it willprobably be possible to make do with one-tenth of the sodium saccharindose due to the very high sweetening power of the sweeteners of formulaI according to this invention.

The compounds of formula I are utilized as acids as well as in the formof their salts with inorganic bases, to serve as sweeteners. Suitablesuch salts include, e.g., sodium, potassium and calcium salts, formed byneutralizing the acid form of compounds having formula I with inorganicbases such as, e.g., sodium hydroxide, sodium carbonate, potassiumhydroxide, potassium carbonate, calcium hydroxide, calcium carbonate,and the like. Compounds having formula I, wherein Hal is an iodine atomare also useful as radio-opaque agents.

The invention also concerns sweeteners comprising a compound of formulaI as sweetening agents and utilized in the form of tablets or as asolution. The sweeteners are produced according to methods known tothose skilled in the art. The compound of formula I is combined with anon-toxic vehicle to produce the sweeteners. For producing the tablets,the procedure is suitably such that a water-soluble auxiliary agent anda water-soluble lubricant (emulsifier) are combined with at least onecompound of formula I and pressed into tablets in a tabletting press.Advantageously, the weight of one tablet is 40 mg to 60 mg, preferably50 mg, the content of active agent then being 5 mg to 15 mg, preferably10 mg, and the content of emulsifier being 0.2 mg to 0.3 mg.

Water-soluble auxiliary agents are compounds which are also tolerated bydiabetics, e.g., fructose, lactose, mannitol, or sorbitol, whereinfructose and lactose are preferred. Lubricants (emulsifiers) arepreferably nonionic emulsifiers, e.g., polyoxyethylene-polyoxypropylenepolymers, polyoxyethylene glycols, ascorbyl palmitate, polyoxyethylatedcompounds, such as polyoxyethylene stearates or polyoxyethylene fattyalcohols, or the ethers thereof, whereinpolyoxyethylene-polyoxypropylene polymer having a molecular weight of6800 and polyethylene glycols having a molecular weight of 6000 arepreferred.

For producing a sweetener solution, at least one compound of formula Iis dissolved in distilled water; optionally, the solution isadditionally combined with a material acting as a thickener in order tofacilitate handling and dosing. The concentration of compounds offormula I in the solution is suitably 10 g to 20 g per liter, 15 g perliter being preferred. Suitable thickeners include, e.g., gelatin,hydroxypropylcellulose, carboxymethylcellulose, water-soluble celluloseethers, 0.1% to 0.8% being contained in the solution. Gelatin andhydroxypropylcellulose are preferred.

The sweeteners of the invention are useful as substitutes for naturalsweeteners, such as sucrose or glucose, especially for persons who mustrestrict their sugar consumption for either medical reasons, e.g.,diabetics, or for dietetic reasons, e.g., to reduce caloric intake. Suchpersons, or animals, will advantageously substitute the sweeteners ofthe invention for at least a portion of the sugar or caloric sweetenersin their diet. For this purpose, they will consume an ingestiblecomposition comprising as a sweetening agent an effective sweeteningamount of a compound of formula I.

The compounds of formula I may be produced by a process wherein

(a) a compound of formula II ##STR11## wherein Hal is a chlorine,bromine or iodine atom and

Z' is the group --COOH, --COOR¹, or ##STR12## wherein R¹ is a hydrogenatom or a lower alkyl residue of 1-4 carbon atoms, and P, K, L, M. N, Xand Y are as defined above for formula I, is partially hydrolyzed to thebenzamide conventionally by reaction with an alkali; or

(b) for preparing compounds of the formula I(A) wherein P is 1, acompound of the formula III ##STR13## wherein Hal is a chlorine orbromine atom, is converted to its alkali metal phenolate and reacted, ina manner known per se, with a compound of Formula IV ##STR14## whereinHal' is a chlorine or bromine atom,

R¹ is a lower alkyl residue of 1-4 carbon atoms, and

K, L, M, N, X and Y are as defined for formula I(A); or

(c) a compound of Formula III, wherein Hal is an iodine atom, isconverted to its alkali phenolate and conventionally reacted with acompound of Formula IV wherein Hal' and R¹ are as defined above, and K,L, M, N, X and Y are as defined for formula I(B) and subsequently, ifdesired, any present carboxylic acid lower alkyl esters are saponifiedand/or salts are produced by reaction with inorganic bases.

Suitable lower alkyl groups R¹ are alkyl residues of 1-4 carbon atoms,the methyl and ethyl residues being preferred.

The partial hydrolysis of the nitrile group to the carbamoyl group,required to produce the compounds of formula I according to thisinvention, is effected by using methods known to those skilled in theart. The term "partial hydrolysis" is meant to denote hydrolysis of thenitrile to an amide function, but not further hydrolysis to the carboxylgroup, which could be considered complete hydrolysis. Thus, the nitrilegroup can be converted into the amide, for example, by dissolving thenitrile precursor in concentrated mineral acids, such as hydrochloricacid, sulfuric acid, or phosphoric acid and conducting the hydrolysis attemperatures of about room temperature to 100° C., preferably at50°-100° C. The nitrile group can, however, also be partially hydrolyzedin an alkaline medium by dissolving or suspending the starting compoundin an aqueous alkali metal hydroxide and hydrolyzing the mixture at atemperature of about room temperature to 100° C., preferably at 40°-80°C.

The starting compounds of formula II required for process pathway (a)are, in part, known or can be prepared using methods known to personsskilled in the art. Thus, for example, compounds of formula II, whereinHal is an iodine atom; Z' is either --COOH or the group ##STR15## and Pand L are 0, are described in German Unexamined Laid-Open ApplicationDOS 2,831,496 together with processes for the preparation thereof.

Compounds of formula II, wherein Hal is a bromine or chlorine atom; Z'is either --COOH or the group ##STR16## and P and L are 0, can beproduced, for example, by reacting an aniline derivative of formula Vwith a halogenating agent, e.g., sulfuryl chloride, in a suitablesolvent such as, for example, benzene, toluene, or ethylene chloride, orwith molecular halogen in a suitable solvent such as, for example,glacial acetic acid or ethylene chloride, to obtain the trihalogenatedaniline of formula VI ##STR17## wherein Hal is a bromine or chlorineatom;

Z' is either --COOH or the group ##STR18## and P and L are 0.

The resultant trihalogenated aniline derivatives of formula VI areconverted, in accordance with the process described in DOS 2,831,496, ina Sandmeyer reaction, by diazotization and subsequent reaction withcyanides into the benzonitriles of general formula II wherein Z' iseither --COOH or the group ##STR19## and P and L are 0.

The following directions for the preparation of3-(3-cyano-2,4,6-trichlorophenyl)propionic acid and for thecorresponding 2,4,6-tribromo compound are set forth to explain theindividual reaction steps.

3-(3-Cyano-2,4,6-trichlorophenyl)propionic Acid

30 g of 3-(3-aminophenyl)propionic acid is suspended in 2 l of benzene,220 ml of sulfuryl chloride is added dropwise thereto, and the batch isheated for 90 minutes to reflux. The product is filtered off underheating from a small amount of undissolved starting material, and thefiltrate is concentrated to dryness. The residue is combined with 900 mlof water and heated under agitation on a steam bath for 1 hour. Then,366 ml of a 25% sodium carbonate solution is added in incrementalportions to the reaction mixture and the latter heated again understirring on a steam bath for 30 minutes. After clarifying the solutionover active carbon, a pH of 2 is set under agitation and cooling byadding concentrated hydrochloric acid. After stirring for several hoursin an ice bath, the precipitate is vacuum-filtered, washed with water,and dried at 50° C., thus obtaining 33 g (68% of theory) of3-(3-amino-2,4,6-trichlorophenyl)propionic acid as a white powder, mp145° C.

7 g of sodium nitrite is introduced under agitation at +5° C. into 84 mlof concentrated sulfuric acid. The mixture is stirred for another 10minutes and then heated to 70° C. to obtain a clear solution. Aftercooling to 5° C., 42 ml of glacial acetic acid is added thereto underice bath cooling. Then, 21.5 g of3-(3-amino-2,4,6-trichlorophenyl)propionic acid is added in incrementalportions at between 0° C. and +5° C., and the mixture is stirred for 2hours at 5° C. The mixture is poured on 200 g of ice and thereafter,under agitation, is introduced into a solution of 35.4 g of copper(I)cyanide and 66.8 g of potassium cyanide in 900 ml of semiconcentratedammonia; during this step, nitrogen is liberated. After stirringovernight at room temperature, 800 ml of ethyl acetate is added and themixture is brought to pH 1 by dropwise addition of concentratedhydrochloric acid. After separating the precipitated inorganic salts byvacuum-filtering, the ethyl acetate phase is removed, washed twice withrespectively 300 ml of water, and evaporated to dryness after dryingover sodium sulfate. Recrystallization from seven times the amount oftoluene yields 16 g (72% of theory) of 3-(3-cyano-2,4,6-trichlorophenyl)propionic acid as a white powder, mp 127°-129° C.

The following compounds are produced analogously:

3-cyano-2,4,6-trichlorophenylacetic acid (mp 182°-184° C.) with a totalyield of 49% of theory, from 3-aminophenylacetic acid (mp 152° C.) viathe intermediate 3-amino-2,4,6-trichlorophenylacetic acid (mp 206° C.)

and

3-cyano-2,4,6-trichlorobenzoic acid (mp 138°-142° C.) with a total yieldof 42% of theory, from 3-aminobenzoic acid (mp 178° C.) via theintermediate 3-amino-2,4,6-trichlorobenzoic acid (mp 159°-161° C.).

3-(3-Cyano-2,4,6-tribromophenyl)propionic Acid

32.7 g of 3-(3-aminophenyl)propionic acid is suspended in 1 liter ofwater and dissolved by adding concentrated ammonium hydroxide, 160 ml ofglacial acetic acid is added thereto, and then a solution of 36 ml ofbromine in 160 ml of glacial acetic acid is added within 2 hours at roomtemperature under thorough agitation. The mixture is stirred for 2hours, the precipitate is vacuum-filtered, washed with water, dried at50° C., and recrystallized from four times the amount of ethyl acetatewith active-carbon treatment, thus obtaining 63 g (78% of theory) of3-(3-amino-2,4,6-tribromophenyl)propionic acid as a white powder, mp195°-197° C.

3.5 g of sodium nitrite is introduced at 5° C. under agitation into 42ml of concentrated sulfuric acid, stirred for 10 minutes, and thenheated to 70° C. until a clear solution is obtained. After cooling to 5°C., 21 ml of glacial acetic acid is added under cooling in an ice bath.Then 16 g of 3-(3-amino-2,4,6-tribromophenyl)propionic acid isintroduced in incremental portions between 0° and 5° C., and the mixtureis agitated for 2 hours at 5° C. The mixture is poured on 200 g of iceand then under agitation is introduced into a solution of 18 g ofcopper(I) cyanide and 33.5 g of potassium cyanide in 450 ml ofsemiconcentrated ammonia, thus liberating nitrogen. The solution issaturated with sodium chloride and stirred overnight under watercooling. The thus-separated ammonium salt is vacuum-filtered anddissolved in the moist state in 200 ml of water. The solution is broughtto pH 1 after treatment with activated carbon, by the addition ofconcentrated hydrochloric acid. After stirring for several hours in anice bath, the precipitate is vacuum-filtered, washed with water, anddried at 50° C., thus producing 13 g (83% of theory) of3-(3-cyano-2,4,6-tribromophenyl)propionic acid as a white powder, mp164°-166° C.

Analogously, the following compounds are prepared:

3-cyano-2,4,6-tribromophenylacetic acid (mp 233° C.) with a yield of 62%of theory, from 3-aminophenylacetic acid (mp 152° C.) via theintermediate 3-amino-2,4,6-tribromophenylacetic acid (mp 229°-231° C.)

and

3-cyano-2,4,6-tribromobenzoic acid (mp 168° C.) with a yield of 75% oftheory, from 3-aminobenzoic acid (mp 178° C.) via the intermediate3-amino-2,4,6-tribromobenzoic acid (mp 180° C.).

For the production of compounds of general formula I, wherein P is 1,according to process pathway (a), the starting compounds areadvantageously the corresponding2,4,6-trihalogen-3-hydroxybenzonitriles, the tribromo and trichlorocompounds being known. The heretofore unknown2,4,6-triiodo-3-hydroxybenzonitrile can be readily prepared byiodination of 3-hydroxybenzonitrile as follows.

To a solution of 11.9 g (100 millimoles) of 3-hydroxy-benzonitrile in130 ml of glacial acetic acid is added over 2 hours a solution of 53 g(327 mmol) of iodine monochloride in 80 ml of glacial acetic acid. After30 minutes, 400 ml of water is added dropwise thereto, and the mixtureis stirred for 24 hours at 35° C. Subsequently, the mixture is cooled toroom temperature and the excess iodine monochloride is decomposed byadding solid sodium bisulfite. The iodination product, removed byvacuum-filtering, is washed with sodium bisulfite solution, then withwater to render the product neutral, and dried. Yield: 31 g (62% oftheory) of 3-hydroxy-2,4,6-triiodobenzonitrile as a cream-coloredpowder, mp 242°-245° C. (decomposition).

The 2,4,6-trihalo-3-hydroxybenzonitriles are then alkylated with thedesired halogen compound of formula IV according to the conventionalprocesses described hereinabove, which are well known in the art.

The following illustrative preparation will further exemplify thealkylation reaction.

3-Cyano-2,4,6-trichlorophenoxyacetic acid methyl ester

22.5 g (0.1 mol) of 3-hydroxy-2,4,6-trichlorobenzonitrile are dissolvedin 240 ml of methanol with the addition of 2.3 g (0.1 mol) of metallicsodium. To the resultant suspension of the sodium salt is added 12.15 ml(0.11 mol) of ethyl bromoacetate, and the reaction mixture is heated toreflux until solution is complete. After filtration over active carbon,the solution is cooled and stirred for several hours in an ice bath. Theresultant crystalline precipitate is vacuum-filtered, washed with alittle ice-cold methanol and dried at 50° C., to produce 19 g (64.5% oftheory) of 3-cyano-2,4,6-trichlorophenoxyacetic acid methyl ester as awhite powder, mp 110°-112° C.

The halogen compounds of formula IV required for the alkylation of theabove-described 2,4,6-trihalo-3-hydroxybenzonitriles as well as of thecompounds of formula III of process pathway (b), described below, aremostly known or can be produced according to conventional processes asdescribed, for example, in European Patent 0001740.

The compounds of formula I, wherein P is 1, are prepared by followingprocess pathway (b), by methods known to persons skilled in the art.Thus, for example, the phenol of formula III, dissolved in a mono- orpolyhydric alcohol, such as methanol, ethanol, glycol, glycerin, butalso diethylene glycol or dimethylformamide, can be converted with theequivalent amount of alkali metal alcoholate into the alkali metalphenolate and by heating, optionally to boiling, with somewhat more thanthe equivalent quantity of alkyl halide of formula IV, can be convertedinto the phenol ether, as known to those skilled in the art. Preferably,when conducting process pathway (b), sodium alcoholate is used as thebase; methanol or ethanol is used as the solvent, and the correspondingchloride or bromide is used as the alkyl halide of formula IV.

However, it is also possible to react the phenol of formula III underboiling in a suitable solvent, e.g., acetone, with an excess of alkalimetal carbonate, preferably potassium carbonate, and the desired alkylhalide of formula IV, which is used in about 10% excess; in thisconnection, addition of alkali metal iodide facilitates the reaction. Ifhigher reaction temperatures are required, higher-boiling ketones can beused, such as methyl ethyl ketone or cyclohexanone. Preferred alkylhalides of formula IV are the chloride or the bromide.

The starting materials of formula III required for conducting processpathway (b) ##STR20## are known with Hal=iodine, e.g., as disclosed inG. Tilly, Chim. Ther., 2(1) 57-65 (1967), or can be prepared from3-hydroxybenzamide by halogenation according to processes known toperson skilled in the art in accordance with the following illustrativedirections.

3-Hydroxy-2,4,6-trichlorobenzamide

25 g (180 mmol) of 3-hydroxybenzamide is dissolved in 500 ml of glacialacetic acid. At 35° C., 26 g of chlorine is then introduced into thesolution and the latter stirred at 60° C. for 4 hours. After evaporationunder vacuum to dryness, the residue is combined with 150 ml of water,stirred for several hours in an ice bath, and the precipitate isvacuum-filtered. After washing with water and drying, 34 g (80% oftheory) of 3-hydroxy-2,4,6-trichlorobenzamide is obtained as a whitepowder, mp 204°-206° C.

3-Hydroxy-2,4,6-tribromobenzamide

40 g (0.29 mol of 3-hydroxybenzamide is suspended in 1.5 l of water anddissolved by adding concentrated ammonia. The solution is then broughtto pH 5 by adding glacial acetic acid, and a solution of 79.9 g (1 mol)of bromine in 200 ml of glacial acetic acid is added thereto dropwiseover two hours at room temperature. The mixture is stirred for twohours, the thus-formed precipitate is vacuum-filtered, washed with 500ml of a 10% sodium bisulfite solution and then with water, and dried at60° C., yielding 103 g (95% of theory) of3-hydroxy-2,4,6-tribromobenzamide as a yellowish-white powder, mp225°-226° C. (decomposition).

If it proves to be necessary during the course of the process of thisinvention to saponify any produced carboxylic acid lower alkyl esters,this is effected by means of methods known to those skilled in the art.Thus, it is possible to suspend the ester in water, to add an excess ofalkali metal hydroxide, and to conduct the saponification at atemperature of 20°-80° C., preferably 50°-70° C. Subsequently thesolution is purified by filtration, preferably over active carbon, andmineral acid is added until an acidic reaction is obtained, whereuponthe acid of formula I can be isolated. To prepare the alkali metalsalts, the acid of formula I is suspended in a suitable solvent, e.g.,in a mixture of ethanol or methanol with water, and converted with theequivalent amount of dilute alkali metal hydroxide, preferably sodium orpotassium hydroxide, into the alkali metal salt; the solution ispurified by filtration, and the salt is isolated.

The examples set forth below will explain the invention in greaterdetail.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1 3-(3-Carbamoyl-2,4,6-trichlorophenyl)propionic Acid

16 g of 3-(3-cyano-2,4,6-trichlorophenyl)propionic acid is dissolved ina solution of 5 g of solution of caustic soda in 80 ml of water. Themixture is maintained at 60° C. for 3 hours, filtered over activecarbon, and the filtrate is brought to pH 1 under cooling by theaddition of concentrated hydrochloric acid under agitation. Afterseveral hours of stirring, the precipitate is vacuum-filtered, washedwith water, and dried at 50° C. Recrystallization from five times theamount of toluene yields 15.5 g (90% of theory) of3-(3-carbamoyl-2,4,6-trichlorphenyl)propionic acid as a white powder, mp196°-198° C.

EXAMPLE 2 3-Carbamoyl-2,4,6-trichlorophenylacetic Acid

As described in Example 1, 3-cyano-2,4,6-trichlorophenylacetic acidyields, with 88% of theory, 3-carbamoyl-2,4,6-trichlorophenylaceticacid, mp 211° C.

EXAMPLE 3 2,4,6-Trichloroisophthalamic Acid

As described in Example 1, 3-cyano-2,4,6-trichlorobenzoic acid results,with a yield of 88% of theory, in 2,4,6-trichloroisophthalamic acid, mp280° C.

EXAMPLE 4 3-(3-Carbamoyl-2,4,6-tribromophenyl)propionic Acid A. AlkalineSaponification

13 g of 3-(3-cyano-2,4,6-tribromophenyl)propionic acid is introducedinto a solution of 3.2 g of caustic soda in 64 ml of water. The solutionis then stirred for 3 hours at 60° C., filtered repeatedly over activecarbon to decolorize, and subsequently the filtrate is brought to pH 1by the addition of concentrated hydrochloric acid. The precipitate isvacuum-filtered, washed with water, and dried at 50° C., thus obtaining16 g (95% of theory) of 3-(3-carbamoyl-2,4,6-tribromophenyl)propionicacid as a white powder, mp 197° C.

B. Acidic Hydrolysis

13 g of 3-(3-cyano-2,4,6-tribromophenyl)propionic acid is suspended in50 ml of concentrated sulfuric acid and heated initially to 60° C. for30 minutes and thereafter to 95° C. for 2 hours. The solution is thenpoured on 300 g of ice and agitated for 3 hours in an ice bath. Thethus-precipitated product is vacuum-filtered, washed with ice water, anddried at 50° C. under vacuum. Yield: 14 g of3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid with 90% of theory,mp 197° C.

EXAMPLE 5 3-Carbamoyl-2,4,6-tribromophenylacetic Acid

As described in Example 4, 3-cyano-2,4,6-tribromophenylacetic acid isused to obtain, with 90% of theory,3-carbamoyl-2,4,6-tribromophenylacetic acid, mp 245° C.

EXAMPLE 6 2,4,6-Tribromoisophthalamic Acid

As described in Example 4, 3-cyano-2,4,6-tribromobenzoic acid yields,with 92% of theory, 2,4,6-tribromoisophthalamic acid, mp>280° C.

EXAMPLE 7 3-(3-Carbamoyl-2,4,6-triiodophenyl)propionic Acid

30 g of 3-(3-cyano-2,4,6-triiodophenyl)propionic acid is introduced intoa solution of 8 g of caustic soda in 100 ml of water. The solution isthen maintained for 3 hours at 60° C., decolorized by repeated treatmentwith active carbon, and brought to pH 1 by adding concentratedhydrochloric acid. After several hours of agitation in an ice bath, theprecipitate is vacuum-filtered, washed with water, and dried at 50° C.Yield: 29 g (94% of theory) of3-(3-carbamoyl-2,4,6-triiodophenyl)propionic acid as a white powder,mp>280° C.

Analogously, the following compounds are obtained from the correspondingnitriles:

2,4,6-triiodoisophthalamic acid

3-(3-carbamoyl-2,4,6-triiodophenyl)-2-ethylpropionic acid

3-(3-carbamoyl-2,4,6-triiodophenyl)acrylic acid

3-(3-carbamoyl-2,4,6-triiodophenyl)-2-n-amyloxypropionic acid

5-(3-carbamoyl-2,4,6-triiodophenyl)pentanoic acid.

EXAMPLE 8 3-Carbamoyl-2,4,6-tribromophenoxyacetic Acid

35.5 g (95 mmol) of 3-hydroxy-2,4,6-tribromobenzamide is suspended in150 ml of methanol and dissolved by adding 2.18 g (95 mmol) of sodium.The mixture is combined with 17.5 g (104 mmol) of ethyl bromoacetate andmaintained under reflux for three hours. After several hours ofagitation, the crystallized product is vacuum-filtered, washed with asmall amount of ice-cold methanol, and dried at 60° C., thus obtaining37.2 g (88% of theory) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acidmethyl ester, mp 231°-233° C.

30 g (67 mmol) of 3-carbamoyl-2,4,6-tribromophenoxyacetic acid methylester is suspended in 300 ml of water, the suspension is heated to 60°C., and the ester is saponified by the dropwise addition of 25 ml ofconcentrated sodium hydroxide solution. The solution is filtered overactive carbon and brought to pH 1 by adding concentrated hydrochloricacid dropwise under ice bath cooling. After several hours of agitation,the thus-formed sediment is vacuum-filtered, washed with water, anddried at 60° C. Yield: 28 g (97% of theory) of3-carbamoyl-2,4,6-tribromophenoxyacetic acid as a white powder, mp271°-272° C. (decomposition).

EXAMPLE 9 4-(3-Carbamoyl-2,4,6-tribromophenoxy)butyric Acid

25 g (66.9 mmol) of 3-hydroxy-2,4,6-tribromobenzamide is suspended in100 ml of methanol and dissolved by adding 1.54 g (66.9 mmol) of sodium.After adding 14 g (73 mmol) of the ethyl ester of 4-bromobutyric acid,the mixture is maintained under reflux for 70 hours, and then thesolution is evaporated to dryness and the residue extracted underboiling with 250 ml of ether. After several hours of stirring in an icebath, the precipitate is vacuum-filtered, washed with ether, and driedat room temperature, thus obtaining 19 g (58% of theory) of4-(3-carbamoyl-2,4,6-tribromophenoxy)butyric acid ethyl ester as a whitepowder, mp 138°-140° C.

18 g (36.9 mmol) of 4-(3-carbamoyl-2,4,6-tribromophenoxy)butyric acidethyl ester is suspended in 180 ml of water and, after adding 10 ml ofconcentrated sodium hydroxide solution, saponified at 60° C. withinthree hours. The solution is filtered over active carbon and brought topH 1 by the dropwise addition of concentrated hydrochloric acid. Afterseveral hours of agitation in an ice bath, the resultant precipitate isvacuum-filtered, washed with water, and dried at 60° C. Yield: 15 g (88%of theory) of 4-(3-carbamoyl-2,4,6-tribromophenoxy)butyric acid as awhite powder, mp 193°-194° C.

EXAMPLE 10 5-(3-Carbamoyl-2,4,6-trichlorophenoxy)-3-oxapentanoic AcidSodium Salt

2.3 g (10 mmol) of sodium is dissolved in 200 ml of ethanol and then 24g (10 mmol) of 3-hydroxy-2,4,6-trichlorobenzamide, 16.7 g (10 mmol) of5-chloro-3-oxopentanoic acid ethyl ester, and 0.3 g of potassium iodideare added to the reaction mixture, and the latter is maintained underreflux for 24 hours. After adding 1 liter of water, the mixture isagitated for 30 minutes in an ice bath, the resultant precipitate isvacuum-filtered and washed with water. Subsequently the moist ethylester of 5-(3-carbamoyl-2,4,6-trichlorophenoxy)-3-oxopentanoic acid issuspended in 250 ml of water and, after adding 40 ml of semiconcentratedsodium hydroxide solution, saponified at 60° C. within three hours. Thesolution is filtered over active carbon, cooled to room temperature, andbrought to pH 1 by adding concentrated hydrochloric acid. After severalhours of stirring in an ice bath, the thus-separated5-(3-carbamoyl-2,4,6-trichlorophenoxy)-3-oxopentanoic acid isvacuum-filtered, washed neutral with water, and then dissolved in 300 mlof a mixture of equal parts of ethanol and water after neutralization bythe addition of 2 N sodium hydroxide solution. The solution is treatedwith active carbon and then concentrated to dryness under vacuum, thusobtaining 29.8 g (82% of theory) of the sodium salt of5-(3-carbamoyl-2,4,6 -trichlorophenoxy)-3-oxapentanoic acid.

EXAMPLE 11 3-Carbamoyl-2,4,6-trichlorophenoxyacetic Acid

16 g (66.9 mmol) of 3-hydroxy-2,4,6-trichlorobenzamide is suspended in100 ml of methanol and dissolved by adding 1.54 g (66.9 mmol) of sodium.After the addition of 16.8 g (66.9 mmol) of bromoacetic acid ethylester, the mixture is maintained under reflux until the reaction iscomplete (TLC control). The product is then concentrated to drynessunder vacuum and the resultant 3-carbamoyl-2,4,6-trichlorophenoxyaceticacid methyl ester is suspended in 100 ml of water. The mixture iscombined with 20 ml of concentrated sodium hydroxide solution andmaintained for 3 hours at 60° C. for saponifying. The solution isfiltered over active carbon, brought to pH 2 by adding concentratedhydrochloric acid, and the precipitate is vacuum-filtered after severalhours of stirring in an ice bath. After washing with water and drying,16.8 g (84% of theory) of 3-carbamoyl-2,4,6-trichlorophenoxyacetic acidis obtained as a white powder, mp 261°-262° C.

EXAMPLE 12 4-(3-Carbamoyl-2,4,6-trichlorophenoxy)butyric Acid

16 g (66.9 mmol) of 3-hydroxy-2,4,6-trichlorobenzamide is suspended in100 ml of methanol and dissolved by adding 1.54 g (66.9 mmol) of sodium.After adding 14 g (73 mmol) of the ethyl ester of 4-bromobutyric acid,the mixture is maintained under reflux for 70 hours; then the solutionis concentrated to dryness and the residue extracted by boiling withether. After several hours of stirring in an ice bath, the crystallizedproduct is vacuum-filtered, washed with ice-cold ether, and dried atroom temperature, yielding 13.4 g (59% of theory) of the methyl ester of4-(3-carbamoyl-2,4,6-trichlorophenoxy)butyric acid as a white powder, mp117°-118° C. The compound is thereafter suspended in 150 ml of waterand, after adding 8 ml of concentrated sodium hydroxide solution,saponified within 3 hours at 60° C. The solution is filtered over activecarbon and brought to pH 2 by adding concentrated hydrochloric acid.After several hours of stirring in an ice bath, the precipitate isvacuum-filtered, washed with water, and dried at 50° C., thus producing11.4 g (89% of theory) of 4-(3-carbamoyl-2,4,6-trichlorophenoxy)butyricacid as a white powder, mp 165°-166° C.

EXAMPLE 13 3-Carbamoyl-2,4,6-triiodophenoxyacetic Acid

0.436 g (19 mmol) of sodium is dissolved in 20 ml of ethanol. Then 9.78g (19 mmol) of 3-hydroxy-2,4,6-triiodobenzamide and subsequently 3.5 g(21 mmol) of ethyl bromoacetate are added thereto. The mixture is heatedfor one hour to reflux and, after several hours of stirring in an icebath, the resultant 3-carbamoyl-2,4,6-triiodophenoxyacetic acid ethylester is vacuum-filtered, washed with a small amount of ice-coldethanol, and suspended in 80 ml of water. The mixture is brought to pH12 by adding concentrated sodium hydroxide solution, stirred for 30minutes at 60° C., the solution is treated with 1 g of active carbon,filtered, and brought to pH 1 by the dropwise addition of dilutehydrochloric acid. After several hours of stirring in an ice bath, thethus-formed precipitate is vacuum-filtered, washed with water, anddried, thus obtaining 10.2 g (89% of theory) of3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp211°-213° C. (decomposition).

EXAMPLE 14 3-Carbamoyl-2,4,6-triiodophenoxyacetic Acid

27.3 g (49 mmol) of 3-cyano-2,4,6-triiodophenoxyacetic acid is stirredin 100 ml of 2 N sodium hydroxide solution for 3 hours at 50° C. Theresultant alkaline solution is filtered over active carbon for purifyingand decolorizing and then brought to pH 2 by adding 2 N hydrochloricacid. After several hours of stirring in an ice bath, the yield is 23.9g (85% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as awhite powder, mp 211°-213° C. (decomposition).

EXAMPLE 15 Preparation of Sweetener Tablets

10 kg of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid sodium salt, 40.75kg of fructose, and 0.25 kg of polyoxyethylene-polyoxypropylene polymer,molecular weight 6800 ("Pluronic" F 68) are mixed together, and themixture is processed into 50 mg tablets. Accordingly, one tabletcontains 10 mg of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid, 40.75 mgof fructose, and 0.25 mg of "Pluronic" F 68.

EXAMPLE 16 Preparation of Sweetener Solution

15 g of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid sodium salt and 3 gof gelatin are dissolved in 250 ml of distilled water; the clearsolution is replenished to 1000 mol with distillated water, and then thesolution is dispensed into dropper bottles.

EXAMPLE 17 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid

29.4 g (0.1 mol) of 3-cyano-2,4,6-trichlorophenoxyacetic acid methylester are suspended in 300 ml of water. After addition of 35 ml ofconcentrated sodium hydroxide, the reaction mixture is heated at 60° C.until a clear solution is obtained. After filtration over active carbon,the solution is cooled and brought to pH 2 by dropwise addition of 50%concentrated hydrochloric acid. The mixture is stirred for 2 hours in anice bath, after which the resultant precipitate is vacuum-filtered,washed with water and dried at 50° C., thus producing 25.4 g (85% oftheory) of 3-carbamoyl-2,4,6-trichlorophenoxyacetic acid as a whitepowder, mp 261°-262° C.

EXAMPLE 18 3-(3-carbamoyl-2,4,6-tribromophenyl)-2-methoxypropionic acid

50 g (223 mmol) of 3-(3-nitrophenyl)-2-methoxyacrylic acid is suspendedin 785 ml of water and brought into solution by the addition of 30 ml ofconcentrated ammonia. After addition of 3 g of Raney nickel, the mixtureis hydrogenated at 80 bar until uptake of hydrogen ceases. The solutionis filtered, 325 g of salt are added, and the resultant solution isthoroughly extracted with tetrahydrofuran. The combined tetrahydrofuranextracts are dried over sodium sulfate, filtered over active carbon andconcentrated, thus producing 38.6 g (88% of theory) of3-(3-aminophenyl)-2-methoxypropionic acid. This product is dissolved in1 liter of water by the addition of 110 ml of 2 N ammonia. The resultantsolution is treated first with 160 ml of glacial acetic acid, and thenwith 36 ml of bromine in 160 ml of glacial acetic acid added dropwise atroom temperature over the course of 2 hours. The reaction mixture isstirred for several hours in an ice bath, the resultant precipitate isvacuum-filtered, washed with water and dried at 50° C., thus producing66 g (73% of theory) of3-(3-amino-2,4,6-tribromophenyl)-2-methoxypropionic acid, as a whitepowder, mp 173°-175° C. 32 g (74 mmol) of this compound is addedportionwise at +5° C. to 80 ml of nitrosylsulfuric acid. Then, 40 ml ofglacial acetic acid is added, and the mixture is stirred for 2 hours at+5° C. The mixture is poured onto 360 g of ice, and the resultantmixture is added to a solution of 33 g of copper(I) cyanide, 62 g ofpotassium cyanide and 464 ml of concentrated ammonia in 297 ml of water,resulting in discharge of gas. The reaction mixture is stirred overnightat room temperature, treated with 1 liter of ethyl acetate, and broughtto pH 2 by addition of concentrated hydrochloric acid. After pressurefiltration, the ethyl acetate phase is separated and the aqueous phaseis again thoroughly extracted with ehtyl acetate. The combined ethylacetate extracts are dried over sodium sulfate, filtered over activecarbon and vacuum-concentrated to dryness, thus producing 24 g of crude3-(3-cyano-2,4,6-tribromophenyl)-2-methoxypropionic acid. This productis hydrolyzed to the amide by stirring at 60° C. in 100 ml of watercontaining 3 g of caustic soda for 3 hours. The resultant solution isfiltered over active carbon and the filtrate is brought to pH 2 withconcentrated hydrochloric acid. The resultant mixture containing aprecipitate is stirred for several hours in an ice bath,vacuum-filtered, washed with water and dried at 50° C., thus producing27.5 g (81% of theory) of3-(3-carbamoyl-2,4,6-tribromophenyl)-2-methoxypropionic acid, as a whitepowder, mp 138°-139° C.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A 3-substituted 2,4,6-trihalogenated benzamidehaving the formula I ##STR21## wherein (A) Hal is a chlorine or bromineatom; andZ is a carboxyl group or the group ##STR22## wherein P and Lare each independently 0 or 1, with the proviso that L is 0 when eitherP or K is 0; K is 0, 2, 3 or 4; M is 0, 1, 2 or 3; N is 0 or 1; X is ahydrogen atom; Y is a hydrogen atom or a lower alkyl group of 1-4 carbonatoms, or when either M or N is other than 0, a hydroxy group, a C₁₋₆alkoxy group or a C₁₋₄ acyloxy group, or when N is 1 and M is other than0, X and Y together form an additional carbon-carbon bond;or wherein (B)Hal is an iodine atom; and Z is a carboxyl group or the group ##STR23##wherein (1) P and L are each 0; K is 0, 2, 3 or 4; M is 0, 1, 2 or 3; Nis 0 or 1; X is a hydrogen atom; Y is a hydrogen atom, a lower alkylgroup of 1-4 carbon atoms, a hydroxy group, a C₁₋₆ alkoxy group or aC₁₋₄ acyloxy group, or when N is 1, X and Y together form an additionalcarbon bond; or (2) P and L are each 1; K is 2, 3 or 4; M is 0, 1, 2 or3; N is 0 or 1; X is a hydrogen atom; and Y is a hydrogen atom or alower alkyl group of 1-4 carbon atoms;or a salt thereof with aninorganic base.
 2. A 3-substituted 2,4,6-trihalogenated benzamideaccording to claim 1, wherein Z is--CH₂ --COOH, --(CH₂)₂ --COOH,##STR24## --O--CH₂ CH₂ --O--CH₂ --COOH, --O--(CH₂)₂ --O--CH₂--CH═CH--COOH.
 3. A 3-substituted 2,4,6-trihalogenated benzamideaccording to claim 1, wherein Y is H, OCH₃, OC₂ H₅, O--n--C₅ H₁₁, CH₃,C₂ H₅, acetoxy or propanoyloxy.
 4. A 3-substituted 2,4,6-trihalogenatedbenzamide according to claim 1, having the formula I(A).
 5. A3-substituted 2,4,6-trihalogenated benzamide according to claim 1,having the formula I(B) (1).
 6. A 3-substituted 2,4,6-trihalogenatedbenzamide according to claim 1, having the formula I(B) (2). 7.3-Carbamoyl-2,4,6-tribromophenoxyacetic acid, a compound of claim
 1. 8.4-(3-Carbamoyl-2,4,6-tribromophenoxy)butyric acid, a compound ofclaim
 1. 9. 3-Carbamoyl-2,4,6-trichlorophenoxyacetic acid, a compound ofclaim
 1. 10. 4-(3-Carbamoyl-2,4,6-trichlorophenoxy)butyric acid, acompound of claim
 1. 11.5-(3-Carbamoyl-2,4,6-trichlorophenoxy)-3-oxapentanoic acid, a compoundof claim
 1. 12. 3-(3-Carbamoyl-2,4,6-tribromophenyl)propionic acid, acompound of claim
 1. 13. 3-(3-Carbamoyl-2,4,6-trichlorophenyl)propionicacid, a compound of claim
 1. 14.3-(3-Carbamoyl-2,4,6-triiodophenyl)propionic acid, a compound ofclaim
 1. 15. 3-(3-Carbamoyl-2,4,6-triiodophenyl)-2-ethylpropionic acid,a compound of claim
 1. 16. 3-Carbamoyl-2,4,6-trichlorophenylacetic acid,a compound of claim
 1. 17. 3-Carbamoyl-2,4,6-tribromophenylacetic acid,a compound of claim
 1. 18.3-(3-Carbamoyl-2,4,6-tribromophenyl)-2-methoxypropionic acid, a compoundof claim 1.